Oxetanes in Drug Discovery Campaigns

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(18), P. 12697 - 12709

Published: Sept. 7, 2023

The oxetane ring is an emergent, underexplored motif in drug discovery that shows attractive properties such as low molecular weight, high polarity, and marked three-dimensionality. Oxetanes have garnered further interest isosteres of carbonyl groups tools to fine-tune physicochemical compounds pKa, LogD, aqueous solubility, metabolic clearance. This perspective highlights recent applications motifs campaigns (2017–2022), with emphasis on the effect medicinally relevant building blocks used incorporate ring. Based this analysis, we provide overview potential benefits appending a compound, well pitfalls, challenges, future directions.

Language: Английский

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Alkene Hydrobenzylation by a Single Catalyst That Mediates Iterative Outer-Sphere Steps

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(4), P. 2351 - 2357

Published: Jan. 17, 2024

Cross-coupling catalysts typically react and unite functionally distinct partners via sequential inner-sphere elementary steps: coordination, migratory insertion, reductive elimination, etc. Here, we report a single catalyst that cross-couples styrenes benzyl bromides iterative outer-sphere metal–ligand-carbon interactions. Each partner forms stabilized radical intermediate, yet heterocoupled products predominate. The system is redox-neutral and, thus, avoids exogenous oxidants, resulting in simple scalable conditions. Numerous variations of alkene hydrobenzylation are made possible, including access to the privileged heterodibenzyl (1,2-diarylethane) motif challenging quaternary carbon variants.

Language: Английский

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Visible Light Photoredox-Catalyzed Decarboxylative Alkylation of 3-Aryl-Oxetanes and Azetidines via Benzylic Tertiary Radicals and Implications of Benzylic Radical Stability

The Journal of Organic Chemistry, Journal Year: 2023, Volume and Issue: 88(10), P. 6476 - 6488

Published: March 3, 2023

Four-membered heterocycles offer exciting potential as small polar motifs in medicinal chemistry but require further methods for incorporation. Photoredox catalysis is a powerful method the mild generation of alkyl radicals C–C bond formation. The effect ring strain on radical reactivity not well understood, with no studies that address this question systematically. Examples reactions involve benzylic are rare, and their challenging to harness. This work develops functionalization oxetanes azetidines using visible light photoredox prepare 3-aryl-3-alkyl substituted derivatives assesses influence heterosubstitution small-ring radicals. 3-Aryl-3-carboxylic acid suitable precursors tertiary oxetane/azetidine which undergo conjugate addition into activated alkenes. We compare oxetane other systems. Computational indicate Giese additions unstrained acrylates reversible result low yields dimerization. Benzylic part strained ring, however, less stable more π-delocalized, decreasing dimer increasing product Oxetanes show high due Bent's rule rendering irreversible.

Language: Английский

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Visible light–mediated aza Paternò–Büchi reaction of acyclic oximes and alkenes to azetidines

Science, Journal Year: 2024, Volume and Issue: 384(6703), P. 1468 - 1476

Published: June 27, 2024

The aza Paternò-Büchi reaction is a [2+2]-cycloaddition between imines and alkenes that produces azetidines, four-membered nitrogen-containing heterocycles. Currently, successful examples rely primarily on either intramolecular variants or cyclic imine equivalents. To unlock the full synthetic potential of reactions, it essential to extend acyclic Here, we report matching frontier molecular orbital energies with those oximes enables visible light-mediated reactions through triplet energy transfer catalysis. utility this further showcased in synthesis

Language: Английский

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Azetidines with All-Carbon Quaternary Centers: Merging Relay Catalysis with Strain Release Functionalization

Journal of the American Chemical Society, Journal Year: 2023, Volume and Issue: 145(34), P. 19049 - 19059

Published: Aug. 17, 2023

Given the importance and beneficial characteristics of decorated azetidines in medicinal chemistry, efficient strategies for their synthesis are highly sought after. Herein, we report a facile elusive all-carbon quaternary-center-bearing azetidines. By adopting well-orchestrated polar-radical relay strategy, ring strain release bench-stable benzoylated 1-azabicyclo[1.1.0]butane (ABB) can be harnessed nickel-catalyzed Suzuki Csp2-Csp3 cross-coupling with commercially available boronic acids broad scope (>50 examples), excellent functional group tolerance, gram-scale utility. Preliminary mechanistic studies provided insights into underlying mechanism, wherein opening ABB catalytic quantity bromide accounts conversion redox-active azetidine, which subsequently engages reaction through radical pathway. The synergistic nickel catalysis could intriguingly derived from single source (NiBr2). Application method to modify natural products, biologically relevant molecules, pharmaceuticals has been successfully achieved as well melanocortin-1 receptor (MC-1R) agonist vesicular acetylcholine transporter (VAChT) inhibitor analogues bioisosteric replacements piperidine azetidine moieties, highlighting potential drug optimization studies. Aside azetidines, demonstrate ancillary utility our system toward restricted tertiary alkyl bromides aryl construct quaternary centers.

Language: Английский

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Improving reproducibility through condition-based sensitivity assessments: application, advancement and prospect

Chemical Science, Journal Year: 2024, Volume and Issue: 15(36), P. 14548 - 14555

Published: Jan. 1, 2024

The fluctuating reproducibility of scientific reports presents a well-recognised issue, frequently stemming from insufficient standardisation, transparency and lack information in publications.

Language: Английский

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Modular Access to Functionalized Oxetanes as Benzoyl Bioisosteres

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(26), P. 18011 - 18018

Published: June 21, 2024

Bioisosterism is a valuable principle exploited in drug discovery to fine-tune physicochemical properties of bioactive compounds. Functionalized 3-aryl oxetanes, as an important class bioisosteres for benzoyl groups (highly prevalent structures approved drugs), have been rarely utilized agrochemicals and pharmaceuticals due significant synthetic challenges. Here, we present modular strategy based on the unexplored yet readily available reagents, oxetanyl trichloroacetimidates, inspired by Schmidt glycosylation, enabling easy access library functionalized oxetanes. This operationally simple protocol leverages vast existing libraries aryl halides various nucleophiles. The power generality this approach demonstrated late-stage functionalization complex molecules, well rapid synthesis oxetane analogues molecules marketed drugs. Preliminary mechanistic study suggests that oxygen atom ring plays crucial role stabilizing carbocation intermediates.

Language: Английский

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C(sp³)−H (N‐Phenyltetrazole)thiolation as an Enabling Tool for Molecular Diversification

Angewandte Chemie International Edition, Journal Year: 2024, Volume and Issue: 63(29)

Published: April 24, 2024

Abstract Methods enabling the broad diversification of C(sp 3 )−H bonds from a common intermediate are especially valuable in chemical synthesis. Herein, we report site‐selective ( N ‐phenyltetrazole)thiolation aliphatic and (hetero)benzylic using commercially available disulfide to access ‐phenyltetrazole thioethers. The thioether products readily elaborated diverse fragment couplings for C−C, C−O, or C−N construction. C−H functionalization proceeds via radical‐chain pathway involving hydrogen atom transfer by electron‐poor ‐phenyltetrazolethiyl radical. Hexafluoroisopropanol was found be essential reactions thiolation, with computational analysis consistent dual bonding radical imparting increased electrophilicity facilitate transfer. Substrate is limiting reagent all cases, reaction displays an exceptional functional group tolerance well suited applications late‐stage diversification.

Language: Английский

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Investigation and optimization of metal- and organocatalyzed decarboxylative radical addition of carboxylic acids to Seebach-Beckwith dehydroalanine towards optically pure unnatural amino acids

Tetrahedron Letters, Journal Year: 2025, Volume and Issue: unknown, P. 155507 - 155507

Published: Feb. 1, 2025

Language: Английский

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Modular Synthesis of 3,3-Disubstituted Azetidines via Azetidinylation Reagents

The Journal of Organic Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: March 19, 2025

Azetidines represent an attractive and emerging design option in medicinal chemistry owing to their small size polar nature, as well potential significantly impact the physicochemical properties of drug molecules. However, traditional methods for synthesis 3,3-disubstituted azetidines usually require higher step counts or exhibit poor functional group compatibility. Herein, we report a modular strategy based on azetidinylation reagents. The practicality this method is further exemplified by use readily available starting materials, mild reaction conditions, very broad substrate scope.

Language: Английский

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